Chen Qiong, Zhu Jianya, Li Xingwang, Wen Ying
State Key Laboratory of Agrobiotechnology and College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Institute of Fisheries Research, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100068, China.
Antibiotics (Basel). 2022 Aug 5;11(8):1065. doi: 10.3390/antibiotics11081065.
Daptomycin, produced by , is a clinically important cyclic lipopeptide antibiotic used for the treatment of human infections caused by drug-resistant Gram-positive pathogens. In contrast to most antibiotic biosynthetic gene clusters (BGCs), daptomycin BGC has no cluster-situated regulator (CSR) genes. DasR, a GntR-family transcriptional regulator (TR) widely present in the genus, was shown to regulate antibiotic production in model species by binding to promoter regions of CSR genes. New findings reported here reveal that DasR pleiotropically regulates production of daptomycin and reddish pigment, and morphological development in deletion enhanced daptomycin production and morphological development, but reduced pigment production. DasR inhibited daptomycin production by directly repressing structural genes and global regulatory gene (whose product AdpA protein activates daptomycin production and morphological development). DasR-protected regions on and contained a 16 nt sequence similar to the consensus DasR-binding site in . AdpA was shown to target structural genes and (which encodes a DeoR-family TR required for daptomycin production). A 10 nt sequence similar to the consensus AdpA-binding site was found on target promoter regions and . This is the first demonstration that DasR regulates antibiotic production both directly and through a cascade mechanism. The findings expand our limited knowledge of the regulatory network underlying daptomycin production, and will facilitate methods for construction of daptomycin overproducers.
达托霉素由[具体产生菌]产生，是一种临床上重要的环状脂肽抗生素，用于治疗由耐药革兰氏阳性病原体引起的人类感染。与大多数抗生素生物合成基因簇（BGCs）不同，达托霉素BGC没有位于簇内的调控基因（CSR）。DasR是一种广泛存在于[具体菌属]中的GntR家族转录调控因子（TR），已证明它通过与CSR基因的启动子区域结合来调控模式菌种中的抗生素生产。此处报道的新发现揭示，DasR多效性地调控达托霉素和红色色素的产生以及[具体菌种]中的形态发育。[具体菌种]中DasR缺失增强了达托霉素的产生和形态发育，但减少了色素的产生。DasR通过直接抑制达托霉素结构基因和全局调控基因[具体基因名称]（其产物AdpA蛋白激活达托霉素的产生和形态发育）来抑制达托霉素的产生。[具体基因1]和[具体基因2]上的DasR保护区域包含一个与[具体参照菌种]中DasR结合位点一致序列相似的16 nt序列。已证明AdpA靶向达托霉素结构基因和[具体基因3]（其编码达托霉素产生所需的DeoR家族TR）。在目标启动子区域[具体区域1]和[具体区域2]上发现了一个与AdpA结合位点一致序列相似的10 nt序列。这是首次证明DasR直接并通过级联机制调控抗生素生产。这些发现扩展了我们对达托霉素生产潜在调控网络的有限认识，并将有助于构建达托霉素高产菌株的方法。
